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Biomedical Optics & Medical Imaging

Laser heating diagnoses and treats cancerous cells

Laser-induced photothermal effects on individual living cells have both diagnostic and therapeutic applications.
17 April 2006, SPIE Newsroom. DOI: 10.1117/2.1200603.0156

When lasers shine on living cells, there is always some heating. Although thermal effects are less familiar than other optical effects such as fluorescence and light scattering, this universal phenomenon offers a potential basis for powerful diagnostic and therapeutic technologies. All living cells contain molecules, such as heme-proteins, that can absorb light. This photo-absorption process can also be enhanced and specified by using gene markers (monoclonal antibodies) attached to strong light absorbers—in this case, metal nanoparticles—that can be selectively delivered into individual cells. Depending on the cell's condition and the laser parameters, the laser-tissue interaction may vary from non-invasive heating or cooling to photodamage.

By analyzing photothermal (PT) phenomena at the cellular level, we discovered large spatial and temporal laser-induced temperature variations at different spots even within a single cell (see Figure 1). These are caused by the non-uniform distribution of light-absorbing molecules in cells, nanoparticles, which may concentrate into nanometer-sized areas, or zones. The initial temperature in such zones may be 100–1000 times higher than average temperature in the cell. While the zones cannot be detected optically, their thermal field spreads over time, becoming larger than the diffraction limit. This allowed us to image the nano-zones through their thermal 'signatures': transient thermal fields and bubbles. When the local initial temperatures reach the evaporation threshold, that part of the cell boils. In other words, the laser induces micro-bubbles that can be easily detected.1,2 These laser-activated bubbles (LAB) can also damage cells. In general, we found that the measurable PT properties of individual cells are very sensitive to their functional and physiological state.3

Figure 1. In photothermal cytometry, a laser pump pulse is absorbed by a cell creating non-uniform thermal effects. These are then registered as a photothermal response or image by a probe laser.

This led us to the idea of probing and monitoring an organism's state by using readily-available particles such as red blood cells. We tested this idea using samples taken from immune-suppressed cancer patients who suffered from sepsis. We found that the PT parameters (such as the probability of creating laser-activated bubbles) of the red blood cells correlate to the patient's clinical outcome (see Figure 2. Specifically, the patients who died due to sepsis 3–5 days after testing showed a LAB probability 1.5–2.0 times lower than the LAB probabilities of either patients or of the control group. At that time, other clinical parameters (leukocyte level, body temperature, C-reactive protein index) did not differ between the three groups.

Figure 2. The bubble-generation probabilities of red blood cells taken daily (shown measured in arbitrary units) are distinctly different for groups of leukemic patients with sepsis who survived (red), and those who died (blue).

We have developed the concept of photothermal cytometry to analyze individual cells by optically monitoring their reaction to a laser pulse. A photothermal time-resolved laser microscope (as shown in Figure 1)1,2,4 uses a pump laser pulse to heat the cell and a coaxial probe laser beam—at the wavelength of minimal absorption—to register the response of the cell. This microscope allows us to image and monitor laser-induced thermal effects—specifically heating and bubble formation—in single intact cells with nanosecond temporal resolution. The PT microscope can also detect nanoparticles with sizes as small as 2nm, which are invisible to optical devices.5 Based on our findings, we suggest a cell-level diagnostic technology: laser-activated bubble cytometry (LABC).3

We also propose a therapeutic method: laser-activated nano-thermolysis as cell elimination technology (LANTCET).6 This novel, chemical-free technology can selectively kill tumor cells by generating laser-activated micro-bubbles around clusters of light-absorbing nanoparticles that target tumor-specific receptors in the cells. Using this new targeting method we can first use the nanoparticles to diagnose tumor cells: see Figure 3(a). Then we can use a laser pulse that generates bubbles around the nanoparticle clusters to cause cell lysis, destroying the tumor cells: see Figure 3(b). This method was tested on bone-marrow samples of leukemic patients and yielded a more that 99% killing efficacy for tumor cells—see Figure 4(b)—at moderate safety for normal cells under the same conditions: see Figure 3(a). LANTCET may allow better selectivity, safety, and control for the laser elimination of residual tumor cells from bone marrow and blood grafts for autologous stem-cell transplantation.

Photothermal cytometry and therapy may find universal and complementary applications due to their high sensitivity and compatibility with existing equipment (microscopes and flow cytometers) and due to the universal nature of photothermal effects. Any living cells can be detected and, when necessary, destroyed in a fast and precise way.

Figure 3. Laser-activated nano-thermolysis as cell elimination technology (LANTCET)is a two-step process. (a) Light-absorbing nanonparticles target (brown) tumor cells but largely ignore normal (blue) cells. (b) A laser pulse heats the nanoparticles, which boil, creating bubbles that destroy the cell membrane.

Figure 4. Shown are optical microscopic images of (a) normal bone marrow cells and (b) common B acute lymphoblasts in a cuvette, after irradiation with a single broad laser pulse with an optical fluence of 1.7J/cm2.

Dmitri Lapotko
Laboratory for Laser Cytotechnologies, Lykov Heat and Mass Transfer Institute
Minsk, Belarus 
Dr. Dmitri Lapotko has researched methods of high-power laser beam control in the atmosphere, biomedical optics, and thermal physics. Since 1991, his main area of research has been laser methods in cell studies. Dr. Lapotko has published over 65 works on this subject. In addition, Dr. Lapotko has given more than 15 presentations at SPIE's BIOS conferences from 1999–2006.